Doxetaxel (DCT) and mitoxantrone (MX) are highly active and potentially synergistic agents in the treatment of metastatic breast cancer (MBC). This pilot study evaluates the combination of dose-dense DCT and MX in patients with MBC to determine the efficacy and toxicity of this therapy. Thirty-six patients (56.1±1.7 years) were studied. The patients received DCT (35 mg/m2q1w) and MX (6 mg/m2 q2w) for 6 weeks of an 8-week interval. Patients with tumor response or stable disease (SD) continued the treatment for a maximum of two additional periods. Hematologic and non-hematologic parameters were determined using the WHO common toxicity score. During this study 14 patients (40%) experienced partial response, 14 (40%) SD. In 20% of the cases the disease progressed on therapy. The treatment with DCT and MX was well tolerated. Seventeen patients (47%) experienced grade 3 leukopenia. Other hematologic and non-hematologic side effects did not exceed grade 2. One patient died during therapy because of a pulmonary embolism, which was unlikely related to active agents. Dose-dense DCT and MX combines both clinical activity and convenience for the patient. Therefore, we conclude that this regimen is a promising therapy in MBC, which warrants confirmation by large-scale clinical trials.